Grant: Operating Grant

Aging researchers still do not know what mechanisms and processes are responsible for aging. Many of the main theories put forward to explain aging have not been well supported by evidence. It now appears that aging is not caused by any single process, but rather by the declining ability of the body to properly regulate many biological processes. This decline arises from the difficulty in maintaining the complex systems necessary for normal functioning, complex systems that involve large numbers of molecules integrated in precisely regulated networks. Although this idea has the potential to explain the aging process, the large number of molecules, the extensive interactions and feedback relationships among them, and the long timescales make experimental approaches unfeasible, and no one has yet tested this "dysregulation" hypothesis of aging. A novel approach is required, one that simultaneously incorporates information about many molecules, their changes over time, and their relationships to each other. This project is the first such approach ever undertaken. It uses hundreds of blood and clinical measures collected in several long-term human datasets. We have access to three of the best such datasets in the world, a unique resource that will allow us to test whether our results can be generalized across different populations. We apply novel statistical methods, including techniques to (a) simplify many measures into fewer, (b) detect a faint signal among noise, and (c) assess causal effects across years. Preliminary analyses have identified multiple new pathways involved in aging and support our hypothesis of dysregulation in aging. The full project will more definitively test this hypothesis, identifying which pathways are involved and how. Understanding biological pathways will in turn allow us to identify social determinants of aging rate, develop clinical tools for measuring patient aging, and further biomedical research on chronic disease pathways.